Progressing the Preclinical Development of P8 for Alzheimer's disease This SBIR competitive Phase IIB renewal application is to continue with the preclinical development of Cenna's lead peptide drug candidate, P8, to treat Alzheimer's disease (AD). There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of A, widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total A production were unsatisfactory as they directly targeted the catalytic activities of - or ?-secretase, enzymes known to hydrolyze other substrates besides APP, many with critical cellular functions. New therapeutic approaches that can inhibit total A production without targeting the activities of the - or the ?- secretase are therefore of great interest. We have a novel technology that does not target the secretases, which has yielded a potential peptide drug candidate, P8, with the ability to inhibit the production of A in vitro and in a transgenic mouse model of AD. P8 is being developed as a new peptide drug for the treatment of AD. In this application we propose to build upon the substantial progress made in the last two years of Phase II funding and to continue with the preclinical development of P8. Specifically, we propose to further develop the formulation of P8 as a subcutaneous injectable drug and carry out investigative non-GLP studies that will provide a toxicological and toxicokinetic assessment of P8 in formulation in order to facilitate its movement into GLP regulatory toxicological testing, which provides a full assessment of the safety profile. Efficacy of P8 in formulation will be assessed in APP transgenic mice. Larger quantities of non-GLP, GLP and GMP grades of P8 will also be synthesized and characterized for the current proposed work and future IND-enabling toxicology and Phase 1 studies.